Liquid chromatography (LC) involves a separation process, which supports chemical analysis and preparation. A typical LC apparatus includes a tube or other vessel packed with a stationary inert porous material; a fluid containing a sample of interest is passed through the porous material. In a typical case, the stationary material includes particles.
More generally, a typical LC system includes a mobile-phase pump, a sample injector, a column, and a detector. The pump propels a mobile-phase fluid along a fluidic path that passes through the injector, column, and detector. The injector introduces a sample into the mobile-phase fluid prior to entry of the fluid into the column.
Typically, mobile-phase solvents are stored in reservoirs, and delivered as required via reciprocating-cylinder based pumps. Sample materials are often injected via syringe-type pumps. For example, some LC systems inject a sample by aspirating (pulling) a fluid-based sample into a tube via a needle or capillary and then pushing the sample into a sample loop. The sample is then injected from the sample loop into the mobile-phase stream on its way to a separation column.
Distinct chemical compounds contained in the fluid often have distinct affinities for the stationary material held in the column. Consequently, as the fluid moves through the chromatographic column, various chemical compounds are delayed in their transit through the column by varying amounts of time in response to their interaction with the stationary porous material in the column. As a result, as the compounds are carried through the medium, the compounds separate and elute from the column over different periods of time.
The different chemical compounds in a sample solution typically separate out as individual concentration peaks in the fluid eluting from the column. The various separated chemicals can be detected by, for example, a refractometer, an absorbtometer, or some other detecting device into which the fluid flows upon leaving the chromatographic column, such as a mass spectrometer.
LC has potential as a tool in support of Process Analytical Technology (PAT). PAT entails apparatus and methods that are employed in support of pharmaceutical manufacturing. A typical PAT system supports analysis and control of manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality. The word “analytical”, with respect to PAT tools, broadly relates to chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner.
In the PAT context, LC is used, for example, to determine when a desired reaction product, e.g., a drug, has begun to appear in a process stream, so that collection of the process stream may commence; LC is also used to determine when collection should cease. The effectiveness of LC analyses are limited, however, by the time delay between collection of a sample, and completion of analysis of the sample. This delay is related to the length of time required to collect a sample and the length of time required to analyze the sample. Analysis time alone can require, for example, a half hour to an hour, for some High-Performance LC (HPLC) equipment. Moreover, LC-based PAT equipment should be reliable and indicate an equipment fault as soon as possible after the fault occurs. Moreover, typical LC equipment does not readily lend itself to PAT support due to difficulty in interfacing the LC equipment to a compound-manufacturing process line.
The location of the output flow of a pharmaceutical-manufacturing process batch, in some cases, is directed through plumbing to accommodate the time lag exhibited by analytical data. After detection of the appearance of the desired compound in the process stream, collection can commence from an appropriate location of the plumbing. Limits in sampling frequency and in speed of sample collection and analysis limit the accuracy in optimal collection of the desired portion of a process stream. Such limits are costly.